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Placebo controlled studies examining clinical problems, e.g. in pain therapy, are considered the "gold standard" for evidence-based medicine. In these studies the placebo effect itself is not the main focus of interest, but serves more as a control for the specificity of the effect of a certain treatment. What physicians in this context often do not realize is that the placebo effect itself represents a true measurable correlate of an organism's psycho-neurobiological response and, thereby, influences the healing process, e.g. the pain relief. Placebo is, therefore, not equivalent to "no treatment". The number of placebo responders, the degree and the duration of the placebo effect is not fixed, but are subject to a much greater variability then hitherto believed. The myth that placebo responders have a certain personality has not been proven correct; instead, the relationships between physicians and patients as well as sociocultural factors have a considerable impact on the placebo effect. Psychological theories explain that classical conditioning, enhanced expectation and motivation of the patient determine the degree of the placebo effect. These directly influence neurobiological systems such as the endogenous opioids which according to modern brain imaging are predominantly activated in pain-relevant areas and contribute to the effect of placebo analgesia. Placebo effects that should be deliberately excluded in controlled clinical trials, can be desirable in clinical practice to optimize the total therapeutic effect. This should mean that the context effect of each therapeutic intervention is maximized towards an improved therapeutic effect, as outlined in the recent AWMF guidelines for postoperative pain therapy, but should not include the administration of an inert substance. The latter is controlled by rigorous ethical guidelines and is only permitted in the context of ethically approved controlled clinical trials. A possible alternative is suggested by Benedetti et al. in which the hidden administration of an active substance identifies the specific response in contrast to the open application of the same substance characterizing the specific plus the placebo effect, after which the pure placebo effect can be determined.